Researchers hope to find the weakness in a parasite that causes ninth largest disease
burden.

A Texas Tech University biology professor received a five-year, $1.6 million grant
from the National Institutes of Health to study the biochemistry of a microscopic
parasite responsible for the tropical disease leishmaniasis in the hope of finding
a cure.

Kai Zhang, an associate professor in the Department of Biological Sciences, said he
will use the funds to study a lipid produced by the protozoa Leishmania to discover
a weakness in the armor of the sometimes deadly parasite, estimated in World Health
Organization literature to cause the ninth largest disease burden among individual
infectious diseases.

“Leishmaniasis is one of those neglected tropical diseases,” Zhang said. “We’re trying
to identify a weak link and go from there. If this eventually leads to a new cure,
that’s a bonus. But even if it fails, it doesn’t mean the work is useless.”

Common in areas such as South America, the Mediterranean, the Middle East and Southern
Asia, the disease is endemic to 88 countries. It’s transmitted by a sandfly, which
is about a third of the size of a mosquito.

The parasitic Leishmania protozoa live in the fly’s gut and can cause anything from
itchy skin irritation or disfiguring ulcers that take months or years to heal to a
deadly attack on the body’s organs.

The World Health Organization estimates about 12 million people are infected with
cutaneous, mucosal or visceral leishmaniasis with 2 million new cases each year. Severity
of the disease is dependent on what species of Leishmania that infects a person and
the host’s genetic makeup, Zhang said. Sometimes, it’s not so much what the parasite
does to the human host that causes the damage as much as the immune system’s response.

About 80 percent of the time, the infection causes lesions on the skin. This less
virulent type is found throughout the world in tropical and sub-tropical areas. Less
common mucosal leishmaniasis tends to affect the mucosal areas of the mouth, nose
and pharynx and can cause severe disfiguration. This form occurs mostly in South and
Central America.

The Institute for OneWorld Health estimates that, worldwide, about 500,000 people
each year contract visceral leishmaniasis, the most deadly form of the disease. More
than 90 percent of these cases happen in India, Bangladesh, Sudan, Brazil and Nepal.
If untreated, the disease is nearly always fatal.

Part of the problem, Zhang said, is that no safe vaccines exist, and the few treatments
for infected patients are outdated and even toxic.

“Right now, there’s no sure cure,” he said. “We have antimony-based compounds as the
frontline drugs. But, they’re dangerous and have been used for more than 50 years.
They have to be administered by injection and have strong side effects. Also, Leishmania
have developed resistance to these drugs. Alternative drugs include pentamindine and
Amphotericin B, which are expensive and difficult to administer. So far, the only
effective oral treatment for leishmaniasis is Miltefosine.”

Zhang and members of his lab are looking at a type of material in the protozoa called
sphingolipids. An enzyme called sphigosinekinase is critical to the metabolism of
sphingolipids, he said, and too much or too little of this enzyme can kill the protozoa.

Leishmania seem to only produce one type of sphingosinekinase, he said. Animals such
as mice produce two, but can survive with only one. Zhang hopes to find a drug that
could inhibit the protozoa enzme, thereby killing the parasite while leaving one of
the two host enzymes intact to continue normal cell function.

“My lab studies Leishmania and how this pathogen causes disease,” Zhang said. “Right
now, we are looking at lipids, which are fairly under-studied because, in the past,
people have thought lipids are just building blocks for the cell membrane. They’ve
concentrated on proteins, nucleic acids and carbohydrates. That’s changed in the last
10 to 20 years. Ultimately, we would like to develop a safe, effective vaccine and
new drugs. So far, the most low-tech, yet most cost-effective way to deal with Leishmania
is to avoid getting bitten by sandflies.”

While the diseases currently are contained to developing nations in tropical or sub-tropical
areas, global climate change, deforestation, human encroachment and human migration
may cause these diseases to thrive in other parts of the world such as the United
States and Europe, he said.

“On one hand, we’re trying to understand the reason why certain proteins or lipids
in Leishmania are important to infection,” Zhang said. “On the other hand, we’re trying
to see if we can we use that knowledge to generate new therapeutics. Right now, the
major challenge is the translation of the data from basic research like what we are
doing in my lab to something that can be used in clinics, such as a new drug or vaccine.”

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